Ground-level ozone is a pervasive toxicant in air pollution that threatens human health. Short-term increases in ozone are associated with increased mortality and hospitalizations in urban communities, and can adversely affect the cardiovascular and pulmonary systems. Emerging epidemiological and experimental evidence supports that ozone exposure is also harmful to the CNS. Ozone-exposure is associated with increased neuroinflammation, oxidative stress, blood-brain barrier disruption, amyloid plaques, and decreased cognitive performance in humans. Similar changes are observed in rodents exposed to ozone, but the molecular mechanisms that contribute to these changes are not completely understood. An important cellular response to oxidative stress and inflammation is activation of the transcription factor Nrf2, which induces expression of antioxidants and cytoprotective proteins. The goal of our research project is to characterize the involvement of the Nrf2 pathway in neuropathological changes caused by ozone exposure. We have found that ozone-exposed mice have increased systemic and pulmonary inflammation that is associated with upregulation of the enzyme BACE1 in the hippocampus. Therefore, overproduction of the Alzheimer's-associated amyloid beta peptide may be a consequence of ozone exposure. Aim 1 will determine whether Nrf2 is activated in the CNS following ozone exposure, and whether Nrf2 knockout mice are more susceptible than wild-type mice to CNS pathologies after ozone exposure. Specifically, we will measure neuroinflammation, blood-brain barrier disruption, oxidative stress, and amyloid beta overproduction in the brain. We will also determine whether Nrf2 knockout mice have elevated pulmonary and systemic inflammation compared to wild-type following ozone exposure, as these effects can be important initiators of CNS pathology. Finally, we will determine whether ozone can more severely impair learning and memory in Nrf2 knockout mice compared to wild-type. Aim2 will determine whether pharmacological upregulation of Nrf2 by sulforaphane or dimethyl fumarate protects against CNS pathologies, systemic and pulmonary inflammation, and learning and memory impairment caused by ozone exposure. Findings of Nrf2-dependent neuroprotection following ozone exposure would have two important implications. First, they would suggest that preexisting Nrf2 dysfunction may render an individual susceptible to harmful effects of ozone on the CNS. Second, they highlight the therapeutic potential of Nrf2-activating compounds to protect against the pathological consequences of ozone exposure.